Pharmacogenetic Optimization of Analgesic Prescribing in Sickle Cell Disease

镰状细胞病镇痛处方的药物遗传学优化

• 批准号: 8190974
• 负责人: Cheedy Jaja
• 金额: $ 9.4万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190974
• 关键词: Absence of pain sensation; Accident and Emergency department; Acute; Acute Pain; Address; Adverse event; Advisory Committees; Algorithms; Analgesics; Biological Markers; CYP2C19 gene; CYP2C9 gene; CYP2D6 gene; Caring; Cessation of life; Clinical; Cohort Studies; Couples; Cytochrome P450; Cytochromes; Data; Development; Dose; Drug Monitoring; Drug Tolerance; Enzymes; Exposure to; Failure; Foundations; Functional disorder; Funding; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Growth and Development function; Incidence; Individual; Inherited; Intervention; Laboratories; Link; Mentored Research Scientist Development Award; Mentors; Metabolic; Mission; Modeling; Monitor; Mutation; National Institute of Nursing Research; Observational Study; Opioid; Opioid Analgesics; Outcome; Pain; Pain Disorder; Pain management; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Phenotype; Play; Prevalence; Principal Investigator; Publishing; Regimen; Research; Research Personnel; Research Support; Research Training; Resources; Risk; Risk Estimate; Risk Factors; Role; Scientist; Sickle Cell Anemia; Susceptibility Gene; Techniques; Testing; Therapeutic; Training; Training Programs; Translational Research; Variant; Visit; adverse outcome; authority; base; career; chronic pain; clinical practice; design; dosage; drug metabolism; experience; high risk; medical schools; mortality; programs; prospective; response; therapy design

DESCRIPTION (provided by applicant): This proposal describes a three year mentored training program for Dr. Cheedy Jaja to create a robust foundation in sickle cell disease (SCD) pharmacotherapy and analgesic pharmacogenetics essential for his transition to an independent translational research scientist with expertise in SCD pain management. A customized program of study that couples didactic coursework and research training with clinical and laboratory training in SCD pathophysiology, pain management and pharmacogenetics is designed. Dr. Abdullah Kutlar, a leading authority in SCD pain management will mentor the principal investigator's scientific growth and development, and an advisory committee of highly regarded SCD researchers and translational scientists will provide scientific and research support. The proposed mentored training draws on the excellent SCD research and clinical resources available at the Medical College of Georgia and encompasses a prospective cohort study. This study seeks to shift clinical practice by challenging the current "as-needed" opioids strategy. Although it is known to exist, the exact incidence and prevalence of suboptimal analgesic prescribing practices in SCD patients is unknown. The absence of this information is a critical barrier to progress in optimizing analgesic therapy. This proposed study approach to addressing this critical barrier is to focus on genetic polymorphisms in cytochrome P450 genes which are known to play a role in analgesic drug metabolism and could help identify patients with higher risk for therapy failure. The study is designed to test the central hypothesis that deficient cytochrome CYP2C9, CYP2C19 and CYP2D6 metabolic phenotypes and suboptimal analgesic prescribing are positively associated with ED visits in SCD patients; and to demonstrate that CYP450 phenotypes information can be used for estimating risks for repeated ED visits for analgesic therapy failure. The Tag-It Mutation Technique is used to determine CYP450 genotypes, and the Medication Quantification Scale is used to determine suboptimal prescribing incidence. The central hypothesis if confirmed, will establish deficient CYP450 phenotypes and exposure to suboptimal prescribing as clinical risk factors. The study risk prediction rules will guide clinicians in identifying individuals who would benefit from targeted, individualized intervention to reduce risks for repeated ED visits. The study will transform current clinical practice deconstructively by demonstrating that suboptimal prescribing is common in SCD analgesic therapy. Constructively, the study will establish feasibility of CYP450 phenotyping for identifying patients likely to achieve successful analgesic relief from conventional analgesic dosing regimens or patients who might benefit from analgesic switching. PUBLIC HEALTH RELEVANCE: This project addresses pain and its management with opioid analgesics in patients with sickle cell disease. By linking suboptimal prescribing of analgesics and deficiency in inherited metabolic capacity in SCD patients to frequent utilization of acute care resources, we may identify possible risk factors for poor pharmacotherapeutic outcomes in SCD patients and validate the need for genotyping to identify at-risk SCD patients for analgesic drugs failure.

描述（由申请人提供）：本提案描述了Cheedy Jaja博士为期三年的指导培训计划，旨在为他过渡到具有SCD疼痛管理专业知识的独立转化研究科学家奠定镰状细胞病（SCD）药物治疗和镇痛药物遗传学的坚实基础。设计了一个定制的学习计划，将教学课程和研究培训与SCD病理生理学，疼痛管理和药物遗传学的临床和实验室培训结合起来。Abdullah Kutlar博士是SCD疼痛管理领域的权威，他将指导主要研究者的科学成长和发展，一个由高度重视的SCD研究人员和转化科学家组成的咨询委员会将提供科学和研究支持。拟议的指导培训借鉴了格鲁吉亚医学院优秀的SCD研究和临床资源，并包括前瞻性队列研究。这项研究旨在通过挑战目前的“按需”阿片类药物策略来改变临床实践。尽管已知存在这种情况，但SCD患者中次优止痛药处方实践的确切发生率和患病率尚不清楚。缺乏这些信息是优化镇痛治疗进展的关键障碍。解决这一关键障碍的拟议研究方法是关注细胞色素P450基因的遗传多态性，已知细胞色素P450基因在镇痛药物代谢中发挥作用，并有助于识别治疗失败风险较高的患者。本研究旨在检验中心假设，即细胞色素CYP 2C 9、CYP 2C 19和CYP 2D 6代谢表型缺陷和次优镇痛药处方与SCD患者的艾德访视呈正相关;并证明CYP 450表型信息可用于估计镇痛治疗失败的重复艾德访视风险。使用Tag-It突变技术确定CYP 450基因型，使用药物定量量表确定次优处方发生率。如果中心假设得到证实，则将确定CYP 450表型缺陷和暴露于次优处方作为临床风险因素。研究风险预测规则将指导临床医生识别将从有针对性的个体化干预中获益的个体，以降低重复艾德访视的风险。该研究将通过证明次优处方在SCD镇痛治疗中很常见来解构性地改变当前的临床实践。在结构上，本研究将确定CYP 450表型分析的可行性，以确定可能从传统镇痛剂给药方案中成功缓解镇痛剂的患者或可能从镇痛剂转换中获益的患者。 公共卫生相关性：该项目涉及镰状细胞病患者的疼痛及其阿片类镇痛药管理。通过将次优的止痛药处方和SCD患者遗传代谢能力缺陷与频繁使用急性护理资源联系起来，我们可以识别SCD患者药物治疗结果不佳的可能风险因素，并验证是否需要进行基因分型来识别高危SCD患者镇痛药物失败。